A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Relafen Warnings, Precautions, Pregnancy, Nursing, Abuse - Nabumetone
Relafen Warnings, Precautions, Pregnancy, Nursing, Abuse - Nabumetone
WARNINGS
Risk of G.I. Ulceration, Bleeding and Perforation with NSAID
Therapy: Serious gastrointestinal
toxicity such as bleeding, ulceration
and perforation can occur at any time, with or without warning symptoms,
in patients treated chronically with NSAID
therapy. Although minor
upper gastrointestinal
problems, such as dyspepsia, are common, usually developing early
in therapy, physicians should remain alert for ulceration
and bleeding in patients
treated chronically with NSAIDs even in the absence
of previous G.I. tract
symptoms.
In controlled, clinical
trials involving 1,677 patients treated with nabumetone (1,140 followed
for 1 year and 927 for 2 years), the cumulative incidence of peptic
ulcers was 0.3% (95% Cl; 0%, 0.6%) at 3 to 6 months, 0.5% (95% Cl;
0.1%, 0.9%) at 1 year and 0.8% (95% Cl; 0.3%, 1.3%) at 2 years.
Physicians should inform patients about the signs and symptoms of
serious G.I. toxicity and what steps to take
if they occur. In patients
with active peptic ulcer,
physicians must weigh the benefits of Nabumetone therapy against
possible hazards, institute an appropriate
ulcer treatment regimen
and monitor the patient's
progress carefully.
Studies to date have not identified any subset of patients not
at risk of developing peptic
ulceration and bleeding.
Except for a prior history of serious G.I. events and other risk
factors known to be associated with peptic ulcer
disease, such as alcoholism, smoking, etc., no risk
factors (e.g., age, sex) have been associated with increased
risk. Elderly or debilitated patients seem to tolerate ulceration
or bleeding less well
than other individuals and most spontaneous
reports of fatal G.I.
events are in this population.
High doses of any NSAID
probably carry a greater risk
of these reactions, although controlled clinical
trials showing this do not exist in most cases. In considering the
use of relatively large doses (within the recommended dosage range),
sufficient benefit should
be anticipated to offset the potential increased risk
of G.I. toxicity.
PRECAUTIONS
General
Renal Effects: As
a class, NSAIDs have been associated with renal
papillary necrosis
and other abnormal
renal pathology during
long-term administration
to animals.
A second form of renal
toxicity often associated with NSAIDs is seen in patients with conditions
leading to a reduction
in renal blood
flow or blood volume,
where renal prostaglandins
have a supportive role
in the maintenance of renal
perfusion. In these patients,
administration
of an NSAID results in dose-dependent decrease in prostaglandin
synthesis and, secondarily,
in a reduction of
renal blood
flow, which may precipitate overt renal
decompensation. Patients at greatest risk
of this reaction are those with impaired renal
function, heart failure,
liver dysfunction, those
taking diuretics, and the elderly. Discontinuation of NSAID
therapy is typically followed by recovery to the pretreatment
state.
Because nabumetone undergoes extensive hepatic
metabolism, no adjustment of nabumetone dosage
is generally necessary in patients with renal
insufficiency. However, as with all NSAIDs, patients with impaired
renal function
should be monitored more closely than patients with normal
renal function
(see CLINICAL PHARMACOLOGY, Special
Studies). The oxidized and conjugated metabolites of 6MNA are
eliminated primarily by the kidneys. The extent to which these largely
inactive metabolites may accumulate in patients with renal
failure has not been
studied. As with other drugs whose metabolites are excreted by the
kidneys, the possibility that adverse reactions (not listed in ADVERSE
REACTIONS) may be attributable to these metabolites should
be considered.
Hepatic Function: As
with other NSAIDs, borderline
elevations of one or more liver
function tests may
occur in up to 15% of patients. These abnormalities may progress,
may remain essentially unchanged, or may return to normal
with continued therapy. The ALT
(SGPT) test is probably
the most sensitive
indicator of liver
dysfunction. Meaningful (3 times the upper limit
of normal) elevations of ALT
(SGPT) or AST (SGOT) have
occurred in controlled clinical
trials of Nabumetone in less than 1% of patients. A patient
with symptoms and/or signs suggesting liver
dysfunction, or in whom an abnormal
liver test
has occurred, should be evaluated for evidence of the development
of a more severe hepatic
reaction while on nabumetone
therapy. Severe hepatic
reactions, including jaundice
and fatal hepatitis, have been reported with other NSAIDs. Although
such reactions are rare, if abnormal
liver tests persist or
worsen, if clinical
signs and symptoms consistent with liver
disease develop, or
if systemic manifestations
occur (e.g., eosinophilia, rash, etc.), nabumetone should
be discontinued. Because nabumetone's biotransformation
to 6MNA is dependent upon hepatic function, the biotransformation
could be decreased in patients with severe hepatic dysfunction.
Therefore, nabumetone should be used with caution in patients with
severe hepatic impairment
(see CLINICAL PHARMACOLOGY, Pharmacokinetics
and Hepatic Impairment .)
Fluid Retention and Edema: Fluid retention
and edema have been observed
in some patients taking nabumetone. Therefore, as with other NSAIDs,
nabumetone should be used cautiously in patients with a history
of congestive heart failure,
hypertension or
other conditions predisposing to fluid
retention.
Photosensitivity: Based on U.V. light
photosensitivity testing, nabumetone may be associated with more
reactions to sun exposure than might be expected based on skin
tanning types.
Information for the Patient
Nabumetone, like other drugs of its class, is not free of side
effects. The side effects
of these drugs can cause
discomfort and, rarely, there are more serious side
effects, such as gastrointestinal
bleeding, which may result in hospitalization
and even fatal outcome.
NSAIDs are often essential
agents in the management of arthritis, but they also may be commonly
employed for conditions which are less serious. Physicians may wish
to discuss with their patients the potential
risks (see WARNINGS
and ADVERSE
REACTIONS) and likely benefits of NSAID
treatment, particularly when the drugs are used for less serious
conditions where treatment
without NSAIDs may represent an acceptable alternative to both the
patient and the physician.
Laboratory Tests
Because severe G.I. tract
ulceration and bleeding
can occur without warning symptoms, physicians should follow chronically
treated patients for signs and symptoms of ulceration
and bleeding, and should inform them of the importance of this follow-up
(see WARNINGS
, Risk of G.I. Ulceration, Bleeding
and Perforation with NSAID
Therapy).
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis, Mutagenesis: In
two-year studies conducted in mice and rats, nabumetone had no statistically
significant tumorigenic
effect. Nabumetone did not wshow
mutagenetic potential
in the Ames test and mouse
micronucleus test
in vivo. However, nabumetone- and 6MNA-treated lymphocytes
in culture showed chromosomal
aberrations at 80 mcg/ml and higher concentrations (equal to the
average human
exposure to nabumetone
at the maximum recommended
dose).
Impairment of Fertility: Nabumetone did not impair
fertility of male or female
rats treated orally at doses of 320 mg/kg/day (1888 mg/m2)
before mating.
Pregnancy, Teratogenic Effects, Pregnancy Category C
Nabumetone did not cause
any teratogenic
effect in rats given
up to 400 mg/kg (2360 mg/m2) and in rabbits up to 300
mg/kg (3540 mg/m2) orally. However, increased post-implantation
loss was observed in rats
at 100 mg/kg (590 mg/m2) orally and at higher doses (equal
to the average human
exposure to 6MNA at
the maximum recommended
human dose). There are no adequate, well-controlled studies in pregnant
women. This drug should
be used during pregnancy only if clearly needed.
Because of the known effect
of prostaglandin-synthesis-inhibiting drugs on the human
fetal cardiovascular
system (closure of ductus
arteriosus), use of nabumetone during the third trimester
of pregnancy is not recommended.
Labor and Delivery
The effects of nabumetone on labor
and delivery in women are not known. As with other drugs known to
inhibit prostaglandin
synthesis, an increased incidence of dystocia
and delayed parturition
occurred in rats treated throughout pregnancy.
Nursing Mothers
Nabumetone is not recommended for use in nursing
mothers because of the possible adverse effects of prostaglandin-synthesis-inhibiting
drugs on neonates. It is not known whether nabumetone or its metabolites
are excreted in human
milk; however, 6MNA is excreted in the milk
of lactating rats.
Pediatric Use
Nabumetone is not recommended for use in children because the safety
and efficacy in children have not been established.
Geriatric Use
Of the 1677 patients in U.S. clinical
studies who were treated with nabumetone, 411 patients (24%) were
65 years of age or older;
22 patients (1%) were 75 years of age
or older. No overall differences in efficacy or safety were observed
between these older patients and younger ones. Similar results were
observed in a 1-year, non-U.S. postmarketing surveillance study
of 10,800 nabumetone patients, of whom 4577 patients (42%) were
65 years of age or older.
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